Adamantyl and adamantylalkyl 2-aminoethyl phosphates, phosphonates and phosphinates

ABSTRACT

The compounds are adamantyl and adamantylalkyl 2-aminoethyl phosphates, phosphonates and phosphinates having renin inhibitory activity.

Unite States Patent Pfeiffer 1 Aug. 1, 1972 [54] ADAMANTYL AND [58] Field of Search ..260/944, 945

ADAMANTYLALKYL Z-AMINOETHYL PHOSPHATES, PHOSPHONATES AND [561 References CM PHOSPHINATES UNITED STATES PATENTS [721 Inventor: minds Cinnaminson, 3,124,508 3/1964 Nordmann ..260/944 x [73] Assignee: Smith Kline & French Laboratories, Primary Examifler joseph Rebold Philadelphia Pa Assistant Examiner-Anton H. Sutto Attorney-William H. Edgerton, Richard D. Foggio, [22] Filed: April 2, 1971 Joan S. Keps, Alan D. Lourie and Joseph A. Marlino [21] Appl. No.: 130,812 ABSTRACT The compounds are adamantyl and adamantylalkyl 2- [52] US. Cl ..260/944, 260/617 R, 260/945, aminoethyl phosphates, h ho ates and phosphin- 260/974 260/978 260/982 260/984 ates having renin inhibitory activity.

260/986, 424/211 [51] Int. Cl. ..C07f 9/08, C07f 9/28, A61k 24/00 4 Claims, No Drawings ADAMANTYL AND ADAMANTYLALKYL 2- AMINOETHYL PHOSPHATES, PHOSPHONATES AND PHOSPHINATFS This invention relates to adamantyl and adamantylalkyl 2-aminoethyl phosphates, phosphonates and phosphinates.

The compounds of this invention have renin inhibitory activity. Renin is an enzyme which is released from the kidney into the bloodstream where it acts upon a substrate, an a-Z-globulin, in blood plasma to form a decapeptide, angiotensin I. A converting enzyme acts upon this substance to produce angiotensin II which is a very potent, pressor substance. A renin inhibitor is therefore useful in reducing blood pressure of renal hypertension.

The activity of the compounds of this invention as renin inhibitors is demonstrated by a biochemical assay procedure. In this procedure, renin substrate is incubated with renin and the compound to be tested, and the angiotensin I formed is hydrolyzed in vitro with converting enzyme to give angiotensin I] and histidylleucine. The amount of histidyl-leucine is then measured spectrophotofluorometrically. Inhibition of the renin catalyzed conversion of renin substrate to angiotensin I is demonstrated by the compounds of this invention at about 2 X M to about 1 X lOM, for example at about 1.7 X 10 M.

The compounds of this invention have coronary vasodilator activity, as indicated by increased coronary blood flow and reduced coronary vascular resistance, and hypotensive activity, demonstrated by administration to anesthetized dogs at doses of from about 5-6 mg/kg. intravenously.

The compounds of this invention are represented by the following formula:

FORMULA I M is hydrogen or an alkali metal cation;

R and R are hydrogen or lower alkyl;

R, is lower alkyl and X is a pharrnaceutically acceptable anion.

Advantageous compounds of this invention are represented by Formula I when R is and, preferably, R is l-adamantyl.

Preferred compounds of this invention are 0-2-(1- adamantyl)ethyl 0-2-aminoethyl phosphate and alkali metal salts thereof, which are represented by Formula I when n is 2, R is l-adamantyl and R is The compounds of this invention are prepared by the 0 n, crmro-immcmom-m in The terms n, R and R are as defined above, m is 0 or 1 and R is amino or lower alkylamino having a N-protecting group such as 2,2,2-trichloroethoxycarbonyl, tbutoxycarbonyl or trityl; phthalimido; di-lower alkylamino; bromo or chloro.

According to procedure I, an adamantanol or adamantylalkanol is reacted with a dichloro 2-substituted ethyl phosphate or phosphonic acid in the presence of a base such as pyridine and when an N-protecting group is present, said group is removed by standard procedures or when R is bromo or chloro, the intermediate is reacted with an optionally N-substituted amine to give the adamantyl or adamantylalkyl optionally N-substituted aminoethyl or quaternary ammoniumethyl phosphate or phosphonate.

According to procedure 11, an adamantanol or adamantylalkanol is reacted with a 2-substituted ethyl phosphate or phosphonic acid and trichloroacetonitrile and when an N-protecting group is present, said group is removed by standard procedures or when R is bromo or chloro, the intermediate is reacted with an optionally N-substituted amine to give the adamantyl or adamantylalkyl optionally N-substituted aminoethyl or quaternary ammoniumethyl phosphate or phosphonate.

R" is hydrogen, methyl or ethyl.

According to procedure lV, an adamantanol or adamantylalkanol is treated with methanesulfonyl chloride or p-toluenesulfonyl chloride, the resulting adamantyl or adamantylalkyl methanesulfonate or p-toluenesulfonate is converted to the adamantyl substituted phosphonic acid by reacting with sodium dimethyl or diethyl phosphonate and then saponifying the resulting esters by treating with acid or base, and then the adamantyl substituted phosphonic acid is reacted with trichloroacetonitrile and a 2-substituted ethanol, and any N-protecting groups are removed or when R is bromo or chloro, the intermediate is reacted with an optionally N-substituted amine to give the optionally N-substituted aminoethyl or quaternary ammoniumethyl ester of the adamantyl substituted phosphomc acid.

Alternatively, the adamantyl substituted phosphonic acid intermediate of procedure IV is prepared by reacting an adamantyl halide or adamantylalkyl halide with sodium dimethyl or diethyl phosphonate and saponifying the resulting esters by treating with acid or base.

According to procedure V, an adamantanol or adamantyialkanol is converted to the corresponding bromide by treating with hydrobromic acid, the bromide is reacted with magnesium and diethylaminodichlorophosphine and the resulting adamantyl substituted diethylamino-chlorophosphine is reacted with hydrogen chloride to give an adamantyl substituted dichlorophosphine which is reacted with a 2-substituted ethanol and when an N-protecting group is present, said group is removed by standard procedures or when R is bromo or chloro, the intermediate is reacted with an optionally N-substituted amine to give the optionally N-substituted aminoethyl or quaternary ammoniumethyl adamantyl substituted phosphinate.

In the above procedures ll to V, the terms n, R R and R are as previously defined.

The procedures for removing N-protecting groups in the above procedures are, for example, treating with zinc in acetic acid to remove the 2,2,2-trichloroethoxycarbonyl group, treating with acid to remove the t-butyloxycarbonyl group or the trityl group and treating with hydrazine to convert the phthalimido group to an amino group.

As indicated in the following examples the products of this invention may be purified by chromatography using adsorbents such as silica gel or Super-Ce] (infusorial earth).

The alkali metal salts are prepared by treating the phosphates or phosphonates with an aqueous solution of an alkali metal hydroxide or bicarbonate, by use of a cation exchange resin or by interchange of a more insoluble salt such as barium or calcium for an alkali metal salt.

The compounds of this invention may be combined with pharmaceutical carriers to form pharmaceutical compositions. in pharmaceutical compositions the phosphates and phosphonates are preferably present as alkali metal salts.

The term lower alkyl where used herein denotes groups having one to four, preferably one to two, carbon atoms.

The following examples are not limiting but are illustrative of compounds of this invention and methods of preparing them.

EXAMPLE 1 A solution of 1.8 g. of 2-( l-adamantyUethanol, 4.5 ml. of anhydrous pyridine and 30 ml. of anhydrous chloroform is added dropwise at 0 C. to a solution of 5.93 g. of dichloro N-(2,2,2-trichloroethoxycarbonyl)- 2-aminoethyl phosphate. The resulting solution is stirred at 25 C. for 18 hours, then diluted with 500 ml. of ether and washed with cold dilute hydrochloric acid and brine. The organic layer is concentrated to give crude 0-2-( l-adamantyl )ethyl 0-2[N-( 2,2,2- trichloroethoxycarbonyl)aminoliethyl phosphate. This material is dissolved in 25 m1. of 90 percent acetic acid and 50 ml. of ether and the resulting solution is treated with 30 g. of activated zinc. The resulting suspension is stirred at 20-25 C. for 3-4 hours. To the suspension is added 60 g. of solid sodium bicarbonate, 6 ml. of water and 100 ml. of chloroform. After stirring for 20-30 minutes, a liter of chloroform and excess sodium sulfate are added and the stirring is continued for another hour. The mixture is filtered and concentrated in vacuo and the residue is chromatographed on one kg. of 2:1 silica gel Super-Cel eluting with chloroform-methanol mixtures. The homogeneous eluates which are obtained with about 40 percent methanol in chloroform are concentrated in vacuo and the residue is recrystallized from chloroformacetonitrile to give 0-2-( l-adamantyl)ethyl 0-2- aminoethyl phosphate, m.p. 243245 C.

A methanol solution of the above prepared phosphate is passed through a cation exchange resin (sodium form) to give, after evaporating the solvent, the sodium salt of 0-2-(1-adamantyl)ethyl 0-2- aminoethyl phosphate.

EXAMPLE 2 A solution of 10.8 g. of 2-( l-adamantyl)ethanol, 10.3 g. of the di-cyclohexylammonium salt of N-( 2,2,2- trichloroethoxycarbonyl)-2-aminoethylphosphoric acid, 28.8 g. of trichloroacetonitrile and 75 ml. of anhydrous pyridine is refluxed for three hours. The solvents are evaporated and the residue dissolved in tetrahydrofuran and stirred with an excess of a cation exchange resin. The solution is evaporated to give, as the residue, 0-2-( l-adamantyl)ethyl 0-2-[N-( 2,2,2- trichloroethoxycarbonyl)amino]iethyl phosphate. This material is dissolved in 75 ml. of acetic acid and 35 ml. of ether, the resulting solution is cooled to C. and 30-35 g. of zinc dust is added gradually and the mixture is stirred for 3.5 hours at room temperature. Then chloroform is added and the mixture is filtered. The filtrate is washed well with water, dried and concentrated and then chromatographed over 700 g. of 2:1 silica gel Super-Cel eluting with chloroform-methanol mixtures to give 0-2-(1-adamantyl)ethyl 0 -2-aminoethyl phosphate, m.p. 243245 C.

EXAMPLE 3 Reacting 2-( l-adamantyl)ethanol with dichloro N- (2,2,2-trich1oroethoxycarbonyl)-2- aminoethylphosphonic acid by the procedure of Example l and treating the resulting 0-2-( 1-adamantyl)ethyl 2-[N-(2,2,2-trichloroethoxycarbonyl)- amino]ethylphosphonate with acetic acid and activated zinc by the procedure of Example 1 gives 0-2-( l-adamantyl )ethyl Z-aminoethylphosphonate.

EXAMPLE 4 A suspension of 3.67 g. of 60.2 percent mineral oil dispersion of sodium hydride. in 100 ml. of tetrahydrofuran is dissolved by the portionwise addition of 17.9 ml. of diethyl phosphonate with stirring under reflux. To the solution is added 3.46 g. of 2-(1- adamantyl)ethyl methanesulfonate [prepared by reacting 2-(1-adamantyl)ethanol with methanesulfonyl chloride in pyridine] in 25 ml. of tetrahydrofuran. The mixture is refluxed overnight, then concentrated under reduced pressure. The residue is dissolved in ether and 403 2-(1-adamantyl)ethylphosphonate.

water and acidified with dilute hydrochloric acid. The aqueous phase is extracted twice with ether. The combined ether extracts are washed with water, dried and concentrated to give the diethyl ester of 2-( l-adamantyl)ethylphosphonic acid.

10.0 Grams of the diethyl ester of 2-( l-adamantyl)- ethylphosphonic acid is heated at 130 C. for 3 hours with 40 ml. of 20 percent aqueous sodium hydroxide solun'on. The reaction mixture is concentrated and the aqueous phase is extracted with ether. The aqueous phase is acidified, extracted with 4:1 ethyl acetatechloroform and the organic extract is washed with brine, dried over sodium sulfate and concentrated. The residue is dissolved in acetone and treated with cyclohexylamine until basic, then cooled to 30 C.

overnight and filtered. The solid material is dissolved in 20 ml. of ethanol and the solution is filtered. The filtrate is concentrated to a small volume and diluted with acetone containing 1 percent cyclohexylamine. The solution is cooled and filtered. The solid material is recrystallized from ethanol-acetone-l percent cyclohexylamine to give 2-( l-adamantyl)ethylphosphonic acid.

A mixture of 3.2 g. of 2-(1-adamantyl)ethylphosphonic acid, 19.2 g. of N-(2,2,2- trichloroethoxycarbonyl)ethanolamine, ml. of pyridine and 20.9 g. of trichloroacetonitrile is heated at 50 C. for 30 hours, then concentrated in vacuo. The residue is diluted with water and extracted with ether. The aqueous layer is acidified and extracted with ether. The ether extracts are combined, washed with water and then concentrated in vacuo. The residue is stirred in 20 ml. of percent acetic acid with 2 g. of activated zinc for 24 hours, then filtered and the filter cake is washed with 4:1 ether-chloroform. The filtrate is washed with water and then chromatographed on 2:1 silica gel Super-Cel, eluting with 9:1 to 7:3 chloroform-methanol mixtures to give O-Z-aminoethyl EXAMPLE 5 A solution of 11.7 g. of 2-(1-adamantyl)ethanol and 75 ml. of a 40 percent solution of anhydrous hydrogen bromide in acetic acid is refluxed for 3 hours, then concentrated to a small volume in vacuo and diluted with water to give 2-( l-adamantyl)-ethyl bromide, m.p. 6869 C.

2-( 1-Adamantyl)ethyl magnesium bromide [prepared from 7.95 g. of 2-(l-adamantyl)ethyl bromide and 0.8 g. of magnesium filings in ml. of ether] is treated with 4.5 g. of diethylaminedichlorophosphine [Chem Ber., 9222681 (1959)] in 50 ml. of ether and the mixture is refluxed for 3 hours, then filtered and fractionally distilled to give diethylamino-2-( 1-adamantyl)ethyl-chlorophosphine. This material is dissolved in anhydrous petroleum ether. The solution is cooled in ice and a stream of dry hydrogen chloride (generated from 2.2 moles of ammonium chloride with sulfuric acid) is introduced with nitrogen as a carrier. The diethylamine hydrochloride is filtered off and 2-(1-adamantyl)ethyl-dichlorophosphine is obtained by fractional distillation at reduced pressure.

Then an additional 2.3 g. of N-(2,2,2-trichloroethoxycarbonyl)ethanolamine is added over 30 minutes and the mixture is stirred for 4 hours at C. and then at room temperature overnight. The mixture is washed with dilute hydrochloric acid, water, percent aqueous sodium bicarbonate solution and water. The solvents are evaporated at 50 C. (0.1 mm.) to give crude 0-2-[ N-( 2,2,2-trichloroethoxycarbonyl)aminolethyl 2-( 1 adamantyl)ethyl phosphinate.

This material is treated with activated zinc and acetic acid by the procedure of Example 1 to give 0-2- aminoethyl 2-( 1-adarnantyl)ethylphosphinate.

EXAMPLE 6 By the procedure of Example 1, using in place of 2- l-adamantyl)ethanol the following:

l-adamantanol Z-adamantanol l-adamantylmethanol 5-( l-adamantyl)pentanol the products are:

0- l-adamantyl 0- Z-aminoethyl phosphate 0-2-adamantyl O-Z-aminoethyl phosphate 0- l -adamantylmethyl O-Z-aminoethyl phosphate 0-5-( l-adamantyl)pentyl O-Z-aminoethyl phosphate.

EXAMPLE 7 3-( l-AdamantyDpropanoic acid is reduced with lithium aluminum hydride in ether to give 3-(l-adamantyl)propanol. Using 3-(l-adamantyl)propanol in place of 2-(l-adamantyl)ethanol in the procedure of Example 1 gives O-3-(l-adamantyl)propyl 0-2- aminoethyl phosphate.

By the same procedure, 4-( l-adamantyl)butyric acid and 6-( l-adamantyl)hexanoic acid are reduced to give 4-( l-adamantyl)butanol and 6-( l-adamantyllhexanol, respectively. Using 4-(l-adamantyi)butanol and 6-( ladamantyl)hexanol in place of 2-( l-adamantyl)ethanol in the procedure of Example 1 gives 0-4-(l-adamantyl)butyl O-2-aminoethyl phosphate and 0-6-(l-adamantyl)hexyl 0-2-aminoethyl phosphate, respectively.

EXAMPLE 8 A solution of 3.1 g. of 2-( l-adamantyhethanol in 35 ml. of dry chloroform and 10 ml. of dry triethylamine is added dropwise to a solution of 12.6 g. of dichloro O-2- bromoethyl phosphate in 10 ml. of dry chloroform at 0-5 C. with stirring. The mixture is allowed to stand overnight in the refrigerator, then stirred for 2 hours and concentrated at room temperature. To the mixture 100 ml. of 0.lN aqueous potassium chloride solution and 40 ml. of 10:1 ether-methanol are added at 0 C. with stirring for 1 hour. The mixture is diluted with 400 ml. of ether and acidified with concentrated hydrochloric acid to pH 2. The ether solution is washed with water, dried over sodium sulfate and concentrated and the residue is azeotroped with benzene to give 0-2-(1- adarnantyl)ethyl 0-2-bromoethyl phosphate.

A solution of 12 g. of dry gaseous trimethylamine in 200 ml. of 2-butanone is added to 6.5 g. of 0-2-( l-adamantyl)-ethyl 0-2-bromoethyl phosphate. The mixture is stirred at50 C. for 18 hours, then concentrated to one-half of its original volume, refrigerated, filtered and dried in vacuo to give 0-2-( l-adarnantyl)ethyl 0-2- (trimethylammonium bromide )ethyl phosphate.

Silver carbonate 10 g. is added to a solution of 4.5 g. of the above prepared ammonium bromide compound with stirring for 3 hours. The mixture is filtered and perculated through a column packed with a 1:1 mixture of weakly basic anion exchange resin (hydroxyl form) and weakly acidic cation exchange resin, eluting with chloroform-methanol to give, after removing the solvent in vacuo, 0-2-( l-adamantyl)ethyl 0-2- (trimethylammonium hydroxide )ethyl phosphate.

EXAMPLE9 According to the procedure of Example 8, 0-2-(1- adamantyl)ethyl 0-2-bromoethyl phosphate is reacted with triethylamirie to give 0-2-( l-adamantyUethyl 0-2- triethylammonium bromide)ethyl phosphate which is converted by the procedure described in Example 8 to O-2-( l-adamantyDethyl O-Z-(triethylammonium hydroxide )ethyl phosphate.

By the same procedure, using tributylarnine in place of triethylarnine, the product is 0-2-(1-adarnantyl)ethyl O-Z-(tributylammonium bromide)ethyl phosphate which is converted to 0-2-(1-adamantyl)ethyl 0-2- (tributylammonium hydroxide)ethyl phosphate.

EXAMPLE 10 Using dichloro 2-bromoethylphosphonic acid in place of dichloro 0-2-bromoethyl phosphate in the procedure of Example 8, the product is 0-2-( l-adamantyl)ethyl Z-(trimethylammonium bromide)ethylphosphonate which is converted by the procedure described in Example 8 to the corresponding hydroxide.

EXAMPLE 11 0-2-( l-adamantyl)ethyl 0-2-(N-ethylamino)ethyl phosphate 0-2-( l-adamantyl)ethyl O-2-(N-butylamino )ethyl phosphate 0-2-( l-adamantyDethyl 0-2-(N,N-

dimethylamino )ethyl phosphate 0-2-( l-adamantyl)ethyl 0-2-(N,N-

dipropylamino)ethyl phosphate 0-2-( l-adamantyl)ethyl 0-2-(N,N-dibutylamino )ethyl phosphate.

EXAMPLE l2 2-(l-Adamantyl)ethylphosphonic acid, prepared as in Example 4, is reacted with N-methyl-N-(2,2,2- trichloroethoxycarbonyl)ethanolamine in the presence of trichloroacetonitrile and pyridine by the procedure M is hydrogen or an alkali metal cation; R, and R are hydrogen or lower alkyl;

R is lower alkyl and X is a pharrnaceutically acceptable anion. 2. A compound according to claim 1 in which R is 3. A compound according to claim 1 in which R is ladamantyl and R is 4. A compound according to claim 1 in which n is 2, R is l-adamantyl and R is I UNITED STATES PATENT @FFICE CE rmmrr Patent No- 3,681,480 Dated Agggst I 1222 Inventor(s) Francis R. Pfeiffer It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

i e e o e i Column 1, line 54, MR X should read N{R X Column 2, an arrow should be inserted pointing from the formula in the right-hand side of column 2, lines 54-56 up to the formula in the left-hand side of column 2, lines 48-50.

Column 9, lines 18-20, in the right-hand side of the column,

-? should be deleted.

Column 9, line 23, the left-hand formula, -O-CH CH -R H should read -F0-CH CH -R OM Signed and sealed this 23rd day of January 1973.

(SEAL) Attest:

EDWARD M.,FLETCHER,JR. ROBERT GOTTSCHALK Attesting Officer Commissioner of Patents 

2. A compound according to claim 1 in which R2 is
 3. A compound according to claim 1 in which R1 is 1-adamantyl and R2 is
 4. A compound according to claim 1 in which n is 2, R1 is 1-adamantyl and R2 is 